Abstract Alcohol Use Disorder (AUD) is a chronic condition characterized by compulsive alcohol use, loss of control over alcohol use, and a negative emotional state when not using alcohol, with such use associated with a range of medical, psychological, social, economic, and personal problems. AUD is global and prevalent; in a survey of over 36,000 adults in the US, AUD had a 12-month prevalence of 13.9%, affecting over 44 million adults in the US in 2015. The total economic cost in the US is estimated at $250-300 billion per year. AUD often goes untreated, possibly partly due to the lack of adequate treatment options; it is estimated that <10% of US adults who meet the criteria for AUD seek help or treatment, and that similarly low percentages of those treated for AUD receive pharmacotherapy. There exists a large unmet medical need for effective treatments for AUD. There are three FDA-approved medications for AUD: disulfiram, oral and long-acting injectable naltrexone, and acamprosate; however, many individuals show limited or no response to these, with poor compliance a factor. Dicerna is developing an siRNA to silence ALDH2 gene expression in liver (DCR-ALDH2) as a treatment for AUD. DCR-ALDH2 has been fully optimized, and significantly reduces ALDH2 in vitro and in liver in intact mice and monkeys, and demonstrated efficacy in a mouse binge drinking model. The goal of this project is to advance DCR-ALDH2 through IND- enabling studies and early clinical testing for AUD. In this U44, we propose five Aims in Phase I, and three Aims in Phase II. In SBIR Phase I, we propose to synthesize non-cGMP drug substance for exploratory studies, develop the relevant assays for downstream activities, and perform dose-range finding PK/PD studies and look at biodistribution in mice and NHPs. These activities should lead to a pre-IND meeting with FDA. In SBIR Phase II, we will synthesize the cGMP lot of drug and conduct IND-enabling toxicology studies in mouse and NHP. Following success with these aims, we will commence a Phase I clinical trial. Our primary outcome measure is safety, as evaluated by occurrence of adverse events or serious adverse events. Our secondary outcome measures include drug PK/PD, and effect of drug on acetaldehyde levels after ethanol administration. Dicerna anticipates having a significant impact on the treatment of AUD by having a long-acting, specific drug with few to no side effects that will improve patient compliance.